ROLE OF EXTRACELLULAR MATRIX IN CARDIOMYOCYTE PROLIFERATION

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。该项目的长期目标是确定细胞外基质（ECM）相互作用在心肌细胞增殖和分化中的作用。哺乳动物的心肌细胞在出生时就失去了增殖能力。因此，在这段时间后死亡的心肌细胞不能被替换，心脏随后失去心脏功能。在围产期，它们增殖表型的变化伴随着心脏的一些其他关键变化。其中包括商业发展和组织，以及ECM的内容和结构。细胞ECM受体，如整合素，介导来自基质的机械和化学信号。在心脏中，这些信号调节许多细胞反应，包括增殖和分化。我们目前正在研究细胞- ecm相互作用用于调节细胞增殖的分子机制，重点关注调节细胞周期的分子。在项目的初始阶段，我们已经确定了不同的ECM成分对心肌细胞DNA合成速率的影响。在该项目的下一阶段，我们将在细胞- ecm相互作用受到干扰的条件下检测肌细胞增殖和特定细胞周期调节因子的表达。最后，我们将通过产生转基因模型，在体内测试上述体外实验所定义的机制。综上所述，细胞- ecm相互作用在心脏细胞的细胞反应调控中起关键作用。这些相互作用如何影响细胞周期的内在调节尚未被研究。本项目的目的不仅是描述心肌细胞增殖的机制，而且还描述了调节心肌细胞发育和永久退出细胞周期的机制。这一信息可能用于心肌细胞重编程，从而完成治疗性修复和替换丢失的心肌细胞。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The long-term objective of this project is to define the role that cell-extracellular matrix (ECM) interactions play in the proliferation and differentiation of cardiac muscle cells. Mammalian cardiac myocytes lose their ability to proliferate around the time of birth. Therefore, cardiac myocytes that die after this time are not replaced and the heart subsequently loses cardiac function. The change in their proliferative phenotype during this perinatal period is accompanied by a number of other critical changes in the heart. Among these are sarcomeric development and organization, and content and structure of the ECM. Cell ECM receptors, such as integrins, mediate mechanical and chemical signals from the matrix. In the heart, these signals regulate a number of cellular responses, including proliferation and differentiation. We are currently investigating the molecular mechanisms that cell-ECM interactions use to regulate cell proliferation, focusing on the molecules that regulate the cell cycle. In the initial phase of the project we have determine the effect that different ECM components have on the rate of DNA synthesis of cardiac myocytes. In the next phase of the project we will assay myocyte proliferation and expression of specific cell cycle regulators under conditions where cell-ECM interactions are perturbed. Lastly, we will test the mechanisms defined by the in vitro experiments described above, in vivo by generating transgenic models. In conclusion, cell-ECM interactions play critical roles in the regulation of cellular responses of heart cells. How these interactions impact upon intrinsic regulators of the cell cycle has not been investigated. The intent of this project is to delineate not only the mechanisms of cardiac myocyte proliferation, but also the mechanisms that regulate their development and permanent withdrawal from the cell cycle. This information could be used to perhaps reprogram cardiac myocytes such that therapeutic repair and replacement of lost cardiac myocyte could be accomplished.